The retinal pigment epithelium (RPE) plays a critical role in maintaining the health and viability of photoreceptor cells. Current evidence implicates RPE dysfunction in the pathogenesis of a variety of retinal degenerative disorders, including age-related macular degeneration (AMD), the most common cause of severe visual loss in the elderly population. The current proposal is aimed at investigating signal transduction within the RPE relevant to photoreceptor-RPE interactions and retinal disease. One line of research is focused on bestrophin, the protein product of the vitelliform macular dystrophy (VMD; Best disease) gene, which we have recently shown to be a chloride channel. VMD is one of several early onset inherited macular degenerations which serve as models for AMD. Investigating the structure, function, and regulation of bestrophin should provide insight into: (1) the signal transduction cascade(s) that mediate light-dependent regulation of RPE function in general and chloride flux in particular, and (2) the pathogenic mechanism of VMD. The second line of research is focused on peropsin, a G-protein-coupled receptor that we discovered several years ago, and that is found only within the apical microvilli of the RPE. We are aiming to: (1) identify the intracellular signaling cascade activated by peropsin, and (2) identify peropsin's ligand.